This application claims priority to U.S. Provisional Application No. 60/183,338, filed Feb. 18, 2000, entitled MOTILIDE COMPOUNDS by inventors Gary Ashley, Mark Burlingame, Chris Carreras, and Daniel Santi, which is incorporated herein in its entirety by reference.
The present invention provides novel prokinetic agents with superior pharmacological and pharmacokinetic properties for the treatment of gastrointestinal motility disorders. The invention relates to the fields of chemistry, medicinal chemistry, medicine, molecular biology, and pharmacology.
Gastrointestinal (xe2x80x9cGIxe2x80x9d) motility regulates the orderly movement of ingested material through the gut to insure adequate absorption of nutrients, electrolytes and fluids. Appropriate transit through the esophagus, stomach, small intestine and colon depends on regional control of intraluminal pressure and several sphincters that regulate forward movement and prevent back-flow of GI contents. The normal GI motility pattern may be impaired by a variety of circumstances including disease and surgery.
Disorders of gastrointestinal motility include, for example, gastroparesis and gastroesophageal reflux disease (xe2x80x9cGERDxe2x80x9d). Gastroparesis is the delayed emptying of stomach contents. Symptoms of gastroparesis include stomach upset, heartburn, nausea, and vomiting. Acute gastroparesis may be caused by, for example, drugs (e.g., opiates), viral enteritis, and hyperglycemia, and is usually managed by treating the underlying disease rather than the motility disorder. The most common causes of chronic gastroparesis are associated with long standing diabetes or idiopathic pseudo-obstruction, often with so-called xe2x80x9cnon-ulcerxe2x80x9d or xe2x80x9cfunctionalxe2x80x9d dyspepsia.
GERD refers to the varied clinical manifestations of reflux of stomach and duodenal contents into the esophagus. The most common symptoms are heartburn and dysphasia; blood loss may also occur from esophageal erosion. GERD may be associated with low tone and inappropriate relaxation of the lower esophageal sphincter and occurs with gastroparesis in about 40% of cases. In most cases, GERD appears to be treatable with agents that reduce the release of acidic irritant by the stomach (e.g., Prilosec) or agents that increase the tone of the lower esophageal sphincter (e.g., cisapride). Other examples of disorders whose symptoms include impaired gastrointestinal motility are anorexia, gall bladder stasis, postoperative paralytic ileus, scleroderma, intestinal pseudoobstruction, gastritis, emesis, and chronic constipation (colonic inertia).
These GI disorders are generally treated with prokinetic agents that enhance propulsive motility. Motilides are macrolide compounds such as erythromycin and its derivatives that are agonists of the motilin receptor. Evidence of the potential clinical utility of motilides includes their ability to induce phase III of Migrating Motor Complexes (xe2x80x9cMMCxe2x80x9d). MMC refers to the four phases (I-IV) of electrical activity displayed by the stomach and small intestine in the fasting state. Muscular contraction occurs in phases III and IV which coincide with a peristaltic wave that propels enteric contents distally during fasting. Other clinically relevant effects include: increase in esophageal peristalsis and LES pressure in normal volunteers and patients with GERD; acceleration of gastric emptying in patients with gastric paresis; and stimulation of gallbladder contractions in normal volunteers, patients after gallstone removal, and diabetics with autonomic neuropathy.
The discovery of motilides was serendipitous. Since the 1950""s, erythromycin A 1 has been known to cause GI side effects such as nausea, vomiting, and abdominal discomfort. These effects are now largely explained by the motilin agonist activity of erythromycin A and an acid catalyzed degradation production, 8,9-anhydro-6,9-hemiacetal 2, which is also known as the enol ether form. 
As illustrated by Scheme A, erythromycin A 1 undergoes an acid catalyzed rearrangement in the stomach to form the enol ether 2 which is then further degraded into the spiroketal 3.Both erythromycin A and the enol ether are motilin agonists but the spiroketal is not. Because the enol ether is approximately ten fold more potent as a motilin agonist than erythromycin A and does not also possess antimicrobial activity, the potential clinical uses of enol ether derivatives as prokinetic agents are being investigated.
Enol ether erythromycin derivatives under clinical investigation include EM-523 (4); EM-574 (5); LY267,108 (6); GM-611 (7); and ABT-229 (8) whose structures are shown below. See U.S. Pat. Nos. 5,578,579; 5,658,888; 5,922,849; 6,077,943; and 6,084,079 which are all incorporated herein by reference. 
Other motilides of potential interest include lactam enol ethers and lactam epoxide derivatives. See also U.S. Pat. Nos. 5,712,253; 5,523,401; 5,523,418; 5,538,961; 5,554,605 which are incorporated herein by reference.
In general, these and other previously disclosed macrolides are synthetically accessible compounds that are derived from erythromycin A or B. Because nature has not optimized the erythromycin structure for its prokinetic activity, it is likely that the potency of motilide agonists could be greatly enhanced. Compounds resulting from such efforts could be of significant benefit in the treatment of wide variety of diseases and conditions. The present invention provides such compounds.
The present invention provides novel macrolide compounds with superior pharmacological and pharmacokinetic properties for the treatment of gastrointestinal motility disorders. In one embodiment, the present invention provides compounds of the formulas 
wherein:
R is hydroxyl or methoxy;
R1 is selected from the group consisting of hydrogen, hydroxyl, halide, NH2, OR9, 
xe2x80x83and 
xe2x80x83where R9 is C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl or heteroaryl and R10 and R11 are each independently hydrogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, or aryl;
R2 and R3 are each independently selected from the group consisting of hydrogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, aryl, alkylaryl, alkenylaryl, alkynylaryl or R2 and R3 together form a cycloalkyl or a cycloaryl moiety;
R4 is hydrogen or methyl;
R5 is hydrogen, hydroxyl, oxo, or together with R6 and the carbons to which they are attached form a cyclic carbonate;
R6 is hydrogen, hydroxyl, OR12 where R12 is C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, or together with R5 and the carbons to which they are attached form a cyclic carbonate;
R7 is methyl, C3-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, alkylaryl, alkenylaryl, alkynylaryl, amidoalkylaryl, amidoalkenylaryl, or amidoalkynylaryl;
R8 is C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, alkylaryl, alkenylaryl, alkynylaryl, amidoalkylaryl, amidoalkenylaryl, or amidoalkynylaryl; and,
x is a single or a double bond. These and other embodiments, modes, and aspects of the invention are described in more detail in the following description, the examples, and claims set forth below.